Abstract 3028: Peroxisome proliferator-activated receptor ≤ (PPARδ) reveals a critical role in promoting the TGFβ-induced EMT and metastasis of non-small cell lung cancer cell (H460)

Abstract

Abstract Although transforming growth factor ≤ (TGFβ) is anti-cancer identified, it was also known to promote tumor malignancy by enhancing the growth, epithelial to mesenchymal transition (EMT), tissue invasion and metastasis in a variety of cancer cells, including non-small cell lung cancers (NSCLCs). The aim of this study was to know the contribution of peroxisome proliferator-activated receptor ≤ (PPARδ) to TGFβ-promoted EMT and metastasis in NSCLCs. The degree of EMT, cell scattering, migration and invasion, and protein expression of PPARδ were first analyzed and compared between H460 and CH27 cells with or without TGFβ treatment (both are NSCLC cell lines). Chemical or shRNA blocking assay was also utilized to further confirm the importance of PPARδ in promoting TGFβ-induced tumor metastasis. Finally, signaling pathway(s) responsible for TGFβ/PPARδ-mediated metastasis was evaluated. The results demonstrated that TGFβ can effectively triggered the EMT, cell scattering, migration and invasion in H460 cell, but only a slight EMT was seen in TGFβ-treated CH27 cell. Meanwhile, PPARδ expression was induced by TGFβ in H460 cells but remained unchanged in CH27 cell. This indicated that PPARδ may involve in TGFβ-mediated metastasis. Co-treatment of TGFβ with GW9662 (a specific PPARδ inhibitor) significantly blocked TGFβ-promoted metastasis of H460 cell indicating the presence of PPARδ was indeed critical for TGFβ-attributed tumor metastasis. TGFβ appeared to act through P38 signaling pathway to trigger the expression of PPARδ and the subsequent activation of epidermal growth factor receptor (EGFR)/c-mesenchymal-epithelial transition factor (c-MET) signaling pathway and the reduction of E-cadherin that eventually led to the EMT and metastasis of H460 cell. Additionally, TGFβ also act through P38 to trigger the expression of β-catenin which could bind to and up-regulate the expression of PPARδ. Blocking of β-catenin activity, however, did not interfere with the metastasis indicating β-catenin may not play a direct role in promoting the metastasis of H460 cell. Nevertheless, we can not preclude the possibility that β-catenin may still act through PPARδ to regulate the metastasis of H460 cell, indirectly. In summary, TGFβ-induced EMT and metastasis in H460 cell was PPARδ-dependent and GW9662 revealed a therapeutical value in the control of NSCLCs (H460). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3028. doi:1538-7445.AM2012-3028